SUMMARY:Adult male circumcision continued to
offer men a high degree of protection against HIV infection
after nearly 5 years, according to long-term follow-up data
from a study in Uganda presented at the 18th Conference on
Retroviruses and Opportunistic Infections (CROI
2011) last week in Boston. A related study found that
elective adult circumcision reduced the occurrence of genital
ulcers by about half, though it had no significant effect
on genital herpes.

During 2005-2006
evidence from 3 large randomized trials conducted in South Africa, Kenya,
and Uganda, showed that elective adult male circumcision reduced the
risk of HIV acquisition by 50% to 60% over the short-term.

In all these
studies, men interested in circumcision were randomly assigned to undergo
the procedure immediately or after a waiting period. All participants
also received regular HIV prevention counseling and free condoms.

The U.S.
National Institutes of Health, which sponsored the trials in Kisumu,
Kenya, and Rakai, Uganda, halted the studies in December 2006 after
an interim
analysis at 24 weeks showed that circumcision reduced the risk of
HIV infection by more than half.

At this
year's CROI, Xiangrong Kong from Johns Hopkins University's Bloomberg
School of Public Health presented findings from extended follow-up of
men in the Rakai trial.

This study
enrolled 4996 HIV negative men aged 15 to 49. After the trial was halted,
men in the control group were offered circumcision as well, and participants
in both the immediate and delayed circumcision groups received ongoing
post-trial surveillance for up to 5 years.

Results

Over
5 years of follow-up, about 80% of men in the initial control group
opted to undergo circumcision.

After
nearly 5 years of surveillance, incidence rates were 0.50 per 100
person-years among all circumcised men versus 1.93 per 100 person-years
among uncircumcised men, a 73% reduction.

An
analysis restricted to original control arm participants who were
circumcised after the randomized trial phase showed a 67% risk reduction.

Men
in the original control arm who opted for circumcision were similar
to those who declined with regard to age, education, marital status,
number of sex partners, condom use, and alcohol use with sex.

Overall,
during post-trial follow-up the 2 groups together reported:

No
change in the number of non-marital sex partners;

10%
decrease in alcohol use with sex;

6%
decrease in any condom use;

4%
decrease consistent condom use.

However, these risk behavior changes did not differ significantly
between circumcised and uncircumcised men.

Based on
these findings, the investigators concluded, "[t]he effectiveness
of male circumcision during a post-trial observational study was comparable
to the efficacy of circumcision for HIV prevention during a randomized
trial."

"Post-trial
male circumcision acceptance was high among controls, with no evidence
of self-selection," they continued. "Condom use declined in
controls both opting for and declining male circumcision, however, the
changes were similar between groups and there was no evidence of risk
compensation associated with circumcision."

Supriya
Mehta(Photo:
Liz Highleyman)

Genital
Ulcer Disease

In the second
presentation, Supriya Mehta from the University of Illinois at Chicago
described further findings from the Kisumu, Kenya, circumcision trial,
which enrolled 2784 men aged 18 to 24 years.

In this
analysis the researchers focused on sexually transmitted infections
other than HIV, looking at genital ulcer disease (GUD) overall, and
at specific causes of GUD including herpes simplex virus type 2 (HSV-2),
syphilis, and chancroid. In several prior studies the presence of genital
ulcers has been shown to increase the risk of both acquiring and transmitting
HIV.

Results

Over
a 24-months follow-up period, circumcision reduced the risk of HIV
infection by 62%.

Overall
GUD incidence fell by 48% among circumcised men compared with uncircumcised
men (2.7 vs 5.2 per 100 person-years, respectively).

HSV-2
incidence did not differ significantly however, with rates of 5.8
per 100 person-years among circumcised men versus 6.1 per 100 person-years
among uncircumcised men, a reduction of only 6%.

Incidence
of syphilis was 23% higher among circumcised men, but this difference
also did not reach statistically significance.

Among
men newly infected with HSV-2, circumcision conferred a stronger
protective effect against GUD, reducing the risk by 67%.

After
controlling for circumcision status, HIV incidence was 3 times higher
among men with incident HSV-2 infection, and almost 6 times higher
among men with GUD.

About
two-thirds of GUD cases -- 63% among circumcised men and 68% among
uncircumcised men -- were not due to HSV-2, and about 40% had no
identifiable infectious cause.

About
one-third of new HIV infections occurred among men who were both
HSV-2 negative and had no GUD.

"Circumcision
halved the risk of GUD among our trial participants, but was not protective
against HSV-2 incidence, even though one-third of genital ulcers were
herpetic," the investigators concluded.

They also
found that "efficacy of [medical male circumcision] against HIV
acquisition was not altered by baseline or incident HSV-2 or GUD."

"In
our population, the protective effect of [medical male circumcision]
against HIV acquisition may be mediated by GUD itself, rather than by
HSV-2," they suggested. "Determining the causes of clinically
detected GUD is necessary to effectively treat and prevent GUD and reduce
associated HIV risk, and to understand how circumcision may confer protection."

At a press
conference discussing the findings, Mehta suggested that some cases
identified as GUD might actually have been due to physical trauma to
the penis, which was about 30% less likely among circumcised compared
with uncircumcised men.

The researchers
were unable to explain, however, why their results differed from those
of the South Africa and Uganda trials, which found that circumcision
was associated with HSV-2 incidence reductions of about 30% and 40%,
respectively.

Abstract 147LB: University of Illinois at Chicago, Chicago, IL; RTI
Internationall, Research Triangle Park, NC; University of Nairobi, Kenya;
University of Manitoba, Winnipeg, Canada; Impact Research and Development
Org, Kisumu, Kenya.